Investigating the relationship between dietary vitamin B12 and bone mineral density: observational and genetic analyses.

Background: Although a potential relationship between dietary vitamin B12 (VB12) and heel estimated bone mineral density (eBMD) has been suggested, the detailed phenotypic and genetic associations that underpin this relationship remain unclear.

Method: We first assessed the phenotypic association between dietary VB12 and eBMD using linear regression and restricted cubic splines based on data from the UK Biobank (N = 64,326). We then explored the genetic relationship between these traits through a large-scale genome-wide cross-trait analysis, leveraging summary statistics from the hitherto largest genome-wide association studies (N_{dietary VB12} = 51,453, N_eBMD = 426,824).

Results: Observational analysis showed no linear association (β = -0.001, P = 0.63) but an inverted U-shaped relationship (P_non-linear = 0.045) of dietary VB12 with eBMD. While no overall genetic correlation was found between dietary VB12 and eBMD, two significant local genetic signals were detected at 13q32.3 and 15q26.1. Cross-trait meta-analysis identified seven pleiotropic single-nucleotide polymorphisms (SNPs) shared between dietary VB12 and eBMD, with two showing colocalization (PPH4 > 0.60). Transcriptome-wide association study revealed one shared gene-tissue pair enriched in Brain-Brodmann Area 9. Although no linear causal association was detected, non-linear Mendelian randomization unveiled a non-linear relationship between dietary VB12 and eBMD.

Conclusion: Both phenotypic and genetic analyses suggest a non-linear association between dietary VB12 and eBMD. The shared genetic basis underlying these traits highlights common biological mechanisms, providing insights for future mechanistic research on nutritional prevention of osteoporosis.